Firstly, DCs subsets from peripheral blood were found quantitatively altered during the first year of disease, but recovered in the second year of progression. Cells were then centrifuged (1600xg, 5 min) and resuspended in serum-free RPMI media. Fadok VA, Voelker DR, Campbell PA, Bratton DL, Cohen JJ, Noble PW, et al. Robb MA, McInnes PM, Califf RM. Briefly, peripheral blood (10 mL) was obtained and monocytes were magnetically isolated using the StraightFrom Whole Blood CD14 MicroBeads kit (Miltenyi Biotech, Bergisch Gladbach, Germany). These signals, called Damage-Associated Molecular Patterns (DAMPs), represent an array of generic motifs that are recognised by a cognate set of humoral factors and peri-cellular receptors which, in turn, instruct the efficient removal of dead cells [1,2]. (2014) 63:3835–45. Data was normalized to MoDCs receiving neither plasmin nor EACA. These analyses suggest that plasmin-mediated immunomodulation involves altered platelet-derived growth factor (PDGF) receptor signalling, IL-2 receptor signalling and Fc-receptor signalling. In this sense, alterations in myDCs and pDCs subsets have been reported in children with T1D at initial stages of disease (29–31), and further efforts are warranted to validate the usefulness of DC subsets as biomarkers in the progression of the disease and to provide further insight into their biological significance. doi: 10.1002/osp4.90, 33. (2006) 26:104–15. doi: 10.2337/db05-1378, 39. This finding was replicated in human DCs from adult patients with T1D (21). In this study, monocyte-derived DCs from pediatric patients with T1D and control subjects were assessed in terms of PS-liposomes capture kinetics, and transcriptional and phenotypic changes. We are grateful for the use of the AMREP Flow Cytometry Facility. On these considerations, we hypothesise that the pro-phagocytic effect of plasmin involves altered PDGF receptor signalling, but this requires further investigation. (2018) 67:1481–94. Blue symbols represent downregulated events. Wrote the paper: RJB ALS MP RLM. As shown in S3 Fig, plasmin caused a significant increase in the number of CD11c+ dendritic cells with internalized microparticles. (2017) 376:1419–29. mmature dendritic cells, that truly excel in this process. The AUC values of patients with established disease were significantly lower than those of patients at onset and control subjects. doi: 10.1016/j.immuni.2011.05.013, 37. and A.L.S. Cells were incubated with proteases, LPS and/or aprotinin (see Fig legends) for 15 min at room temperature. (2012) 35:2303–10. On the one hand, efferocytosis of apoptotic beta cells was mimicked using previously-described synthetic microvesicles displaying features of apoptotic cells (20). (1984) 83:321–9. doi: 10.1083/jcb.201004096, 7. Then, monocytes were magnetically isolated directly from whole blood, and differentiated into DCs in vitro. Front. All the experiments were carried out in strict accordance with the principles outlined in the Declaration of Helsinki for human research and after the approval of the Committee on the Ethics of Research of the Germans Trias i Pujol Hospital. Importantly, the expression of tolerogenic markers was also found upregulated in adult DCs after the capture of PSAB-liposomes in our previous RNA-seq analysis (21). Previous studies have shown that plasmin has a pro-inflammatory influence on macrophages [11–15] and increases their capacity to phagocytose apoptotic cells [16]. Affiliation Incidence trends of type 1 and type 2 diabetes among youths, 2002–2012. This happening would increase the availability of danger signals and feed the autoimmune process against beta cells. In conclusion, T1D progression in childhood entails altered peripheral blood DCs subsets, as well as impaired DCs phagocytosis, although tolerance induction could still function optimally. After 6 days, DCs differentiation yield was assessed by CD11c-APC staining (Immunotools, Friesoythe, Germany) and viability was determined by annexin V-PE (Immunotools) and 7-AAD (BD Biosciences) using FACSCanto II (BD Biosciences). We would like to thank Ms Chindu Govindaraj for organising the delivery of buffy coats from the Australian Red Cross Blood Bank and Mr Mutsa Madondo, Department of Immunology, Monash University for assistance with the immunostaining of human MoDCs. SR-F, FV, and MV-P designed the experiments. ANOVA was used for comparisons with several factors. (2015) Dendritic Cell-Mediated Phagocytosis but Not Immune Activation Is Enhanced by Plasmin. Countless factors can potentially impact on the proper functionality of the DCs, which range from altered subset distribution, impaired phagocytic function to abnormal gene expression. These studies showed that plasmin-treatment alone did not alter IL-6 (Fig 3A), IL-10 or IL-12 levels (S1 Fig) suggesting that plasmin does not cause MoDC maturation. No use, distribution or reproduction is permitted which does not comply with these terms. Dendritic cells (DCs), named for their probing, ‘tree-like’ or dendritic shapes, are responsible for the initiation of adaptive immune responses and hence function as the ‘sentinels’ of the immune system. Pujol-Autonell I, Serracant-Prat A, Cano-Sarabia M, Ampudia RM, Rodriguez-Fernandez S, Sanchez A, et al. Macrophages are known as big eaters in the immune system since they are the main immune cells which eat pathogens and cell debris and clean the body. Data was normalized to the values for untreated cultures and detergent-treated cultures. Their clinical data are summarized in Table 1. LPS also increased migration of conventional dendritic cells and Langerhans cells to the draining lymph nodes (Fig 6). Significantly altered 'short-listed' proteins are highlighted where Pink represents up-regulated phospho-proteins; Blue represents down-regulated phospho-proteins. (2018) 111:194–205. The objective of our study was to compare the abilities of polymorphonuclear neutrophilic leukocytes (PMN), monocytes, monocyte-derived macrophages (MDM), monocyte-derived immature DC (imDC), and mature DC … After 48 h, the concentration of IL-6 (Panel A) and TGF-β (Panel B) in the conditioned media was determined. Confocal micrographs were taken on a Nikon A1r-si resonant scanning confocal system (microscope: Nikon Ti; objective: Apo LWD, 40x magnification, 1.15 numerical aperture, water immersion; sequential excitation: 405 nm, 488 nm and 546 nm laser lines; respective emission filters: 450/50 nm, 525/50 nm and 595/50 nm; photomultiplier tube detectors; acquisition software: NIS elements Advanced Research). Golpon HA, Fadok VA, Taraseviciene-Stewart L, Scerbavicius R, Sauer C, Welte T, et al. (2019) 10:148. doi: 10.3389/fimmu.2019.00148, 28. Adherent cells (monocytes) were washed and incubated with 6 mL of AIM-V media plus 1% heat-inactivated autologous serum, 200 U/mL human rIL-4 and 500 U/mL human rGM-CSF for 4–5 days under humidified 5% CO2 conditions. Articles, Icahn School of Medicine at Mount Sinai, United States. Dendritic Cells. Front Immunol. (2017) 12:1231–42. Differences were found between groups (*p < 0.05, **p < 0.01, Mann-Whitney test). Protease inhibitor tablets for cell lysis were from Roche (Mannheim, Germany). For correlation between parameters, Spearman's test was used. One salient point is whether endogenous plasmin(ogen) levels increase in the interstitial space to a concentration that influences dendritic cells in vivo. An example of this includes the interaction of the membrane proteins of the B7 family of the dendritic cell with CD28 present on the lymphocyte. Phagocytosis Is Required for Dendritic Cell Inflammatory Cytokine Response to Gut Commensal Yeast Saccharomyces cerevisiae. Even if the three cell types phagocytose parasites, bacteria, cell debris, or even intact cells very efficiently, the functional outcomes of the phagocytic event are quite different. Indeed, plasminogen is actively transported to sites of injury by macrophages/neutrophils (rather than by non-specific accumulation due to vessel leakage) [15]. Data were normalized to the groups where MoDCs received neither plasmin nor inactive plasmin. Phosphatidylserine-liposomes promote tolerogenic features on dendritic cells in human type 1 diabetes by apoptotic mimicry. Overall, these results suggest that DCs from patients could mediate immunoregulatory attempts. Given the pro-inflammatory role of plasmin, we propose that the ability of plasmin to simultaneously suppress the immune response would be relevant during sterile tissue injury where large-scale protective inflammatory responses need to occur alongside the immunologically-discrete removal of cell debris. No, Is the Subject Area "Flow cytometry" applicable to this article? Accordingly, to assist the future identification of putative signalling events that may underlie plasmin-mediated immunomodulation, we performed a kinomic screen whereby MoDCs were treated with/without plasmin for 3 h, after which cell lysates were harvested and subjected to Kinexus antibody microarray (which utilises ~500 pan- and ~340 phospho-specific antibodies). Thus, the proteolytic activity of plasmin promotes the phagocytosis of necrotic cells. Kassem SA, Ariel I, Thornton PS, Scheimberg I, Glaser B. Beta-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Nature. To explore whether plasmin could similarly modulate dendritic cell function in vivo, fluorescent microparticles were injected intradermally into the base of the tail of wild-type mice in the presence or absence of t-PA and plasminogen (alone or in combination). As for the immunoregulatory profile, DCs from pediatric patients with T1D showed higher expression of PPARG and TGFB1—two genes downstream in the efferocytosis signaling pathway—than control subjects. For assessment of the maturation of human MoDCs, the antibodies used were: PE/APC-conjugated mouse anti-CD40 (clone 5C3), PE-conjugated mouse anti-CD70 (clone Ki-24), PE/Biotin-conjugated mouse anti-L307.4, FITC/APC-conjugated mouse anti-HLA-DR (clone G46-6[L243]), FITC-conjugated mouse anti-Human CD274 (clone MIH1), PE/APC/Biotin-conjugated mouse IgG1 isotype control (clone MOPC-21) and PE/APC/Biotin-conjugated mouse IgG2a isotype control (clone G155-178). Indeed, we believe these are paramount aspects to consider in the near future, when antigen-specific immunotherapies will be available and immunomonitoring of the patients will be required. Cell Immunol. Mice were euthanized with urethane. Pediatric patients with T1D (n = 61) were visited as outpatients or hospitalized in the Pediatric Section at Germans Trias i Pujol Hospital. Department of Allergy, Immunology and Respiratory Medicine, Alfred Medical Research and Education Precinct, Melbourne, 3004, Victoria, Australia. Immune dysfunction in patients with diabetes mellitus. Reagents were from Life Technologies unless indicated otherwise. Hence, the ability of plasmin to promote particle uptake is selective for the actin-dependent pathway of phagocytosis, and not the result of a general enhancement of endocytic capacity. VEGFA secretion by DCs was determined in culture supernatant by ELISA (ThermoFisher Scientific). (2018) 9:253. doi: 10.3389/fimmu.2018.00253, 22. Mediators Inflamm. Dendritic cells are a vital component of the innate immune system, which constitutes the body's first line of defense against infectious agents and tumor cells. Heat-inactivated foetal calf serum (FCS; 200 μL) was added and incubated for 1 min. Interestingly, the observed plasmin-mediated increase in microparticle uptake was only mildly attenuated by EACA (a lysine analogue) after 24 h (Fig 2C) of co-incubation. Secondly, to study the tolerogenic functionality of DCs, liposomes with phosphatidylserine (PS) were designed to mimic apoptotic beta cells, which are able to induce tolerance, as previously demonstrated by our group in DCs from adult patients with T1D. Davidson NJ, Sowden JM, Fletcher J. Henson PM. Concentration of IL-6, TNF-α, IL-10, and VEGFA secreted by DCs obtained from control subjects (white squares, n ≥ 3), patients with T1D at onset (white circles, n ≥ 3) and patients with established disease (black dots, n ≥ 3). Elliott MR, Ravichandran KS. Virology. Patients at second year of progression required higher insulin doses than patients at onset and at first year of evolution. This immunotherapy arrested autoimmunity upon administration to NOD mice after PS-liposomes were phagocyted by DCs, thus eliciting tolerogenic features. Human and mouse plasmin were from Hematologic Technologies (Essex Junction, Vermont, USA). As a first approach, different subsets of circulating DCs were assessed in control subjects and patients with T1D at diagnosis, and at first year and second year of progression. The importance of plasmin to the modulation of dendritic cell function should now be assessed in disease settings such as burns and cancer – instances where immunosuppression [44] and substantial binding of t-PA/plasminogen to necrotic tissue [45] are commonplace. doi: 10.2337/db14-0365, 45. Nat Rev Cancer. Breakdown of the plasma membrane during necrosis exposes NCC-protein aggregates, which bind t-PA and plasminogen and promotes in situ plasmin formation [8] allowing proteolytic degradation of NCC-aggregated proteins. Taking into account the many recent advances in DC biology, we discuss how DCs (1) recognize pathogenic antigens with pattern recognition receptors through specific phagocytosis and through non-specific micropinocytosis, (2) process antigens into small peptides with proper sizes and … After observing alterations in DCs subsets in pediatric patients with T1D, and in order to assess their functionality, DCs were derived from peripheral blood monocytes from patients at diagnosis and with established disease as well as from control subjects. In patients with type 2 diabetes, there is growing evidence that impaired phagocytosis in neutrophils (17, 18) and macrophages (19) is related to glycemic control, albeit it can be alleviated with improved metabolic regulation. The observation that plasmin-treatment markedly increased total TGF-β levels was intriguing since plasmin is known to proteolytically activate TGF-β [27], and because TGF-β is a potent immunosuppressant of downstream lymphocyte activation [28,29]. We now wanted to determine whether plasmin formed on the surface of dead cells also influences their clearance via phagocytosis. (A) Uninjured and necrotic Jurkat lymphocytes were stained with 10 mg/L 7AAD and 10 mg /L Thiazine Red for 15 min then subjected to flow cytometry. Hematopoiesis occurs in yolk sac during 1 st week of gestation. (DM). (C) Area under the curve (AUC) of phagocytosis kinetics curves. Biomarkers and surrogate endpoints: developing common terminology and definitions. Cells were washed twice with RPMI media +10% FCS and then twice with PBS. Membrane expression of PS receptors such as CD36, TIM4 and Integrin αvβ5 was not altered after liposome capture in comparison to iDCs. The immune cell type that initiates the early immune response to T. pallidum thus far has not been identified. Plasmin-treated dendritic cells did not undergo maturation and showed reduced migration to the draining lymph node. No significant differences were found when comparing culture conditions in the same group (Wilcoxon test). A surprising observation was that plasmin also attenuated the ability of dendritic cells to mount an adaptive immune response. We are grateful to Mr. M. Fernandez (IGTP) for his support in flow cytometry and to Ms. D. Culell-Young for English grammar assistance. First, the viability of DCs from all groups was higher than 90% in all conditions, thus confirming that PS-liposomes are not toxic to DCs obtained from pediatric subjects (data not shown). doi: 10.2337/db12-0397, PubMed Abstract | CrossRef Full Text | Google Scholar, 3. doi: 10.1016/0008-8749(84)90311-3, Keywords: dendritic cells, immune tolerance, type 1 diabetes, phagocytosis, autoimmunity, Citation: Rodriguez-Fernandez S, Murillo M, Villalba A, Perna-Barrull D, Cano-Sarabia M, Gomez-Muñoz L, Aguilera E, Maspoch D, Vazquez F, Bel J and Vives-Pi M (2019) Impaired Phagocytosis in Dendritic Cells From Pediatric Patients With Type 1 Diabetes Does Not Hamper Their Tolerogenic Potential. In-house control experiments verified that the responder cells were viable and responsive to stimulation in these experiments. Table 1. PKH26 and PKH67 positive MoDCs) analysed by flow cytometry (BD FACS Calibur). here. Flow cytometry data was analysed using FlowJo software version 9.4 (Tree Star Inc, Ashland, OR, USA). The resultant cells were cultured at 1x106 cells/mL in complete medium (RPMI media +10% FCS, 4 mM L-glutamine, 100 U/mL streptomycin/penicillin, 20 mM HEPES pH7.4) supplemented with 20 ng/mL mouse rGM-CSF and 20ng/mL mouse rIL-4. White squares are control subjects (n = 5), white circles are patients at onset (n = 3-5), and black dots are patients with established disease (n = 6). Dead cells facilitate their innocuous removal via the presentation of signals that engage pro-degradation enzymes and promote phagocytic clearance. Necrotic cells were generated by heat-treating human Jurkat lymphocytes. The mononuclear phagocyte system (MPS) has historically been categorized into monocytes, dendritic cells and macrophages on the basis of functional and phenotypical characteristics. Together with an increased phagocytic capacity, plasmin-treated dendritic cells maintain an immature phenotype, exhibit reduced migration to lymph nodes, increase their expression/release of the immunosuppressive cytokine TGF-β, and lose their capacity to mount an allogeneic response. Moreover, this increase in phagocytosis did not result in maturation, as determined by CD86 expression (Fig 6; middle panels). Plasmin cleaves and thereby reduces the expression of numerous cell-surface immunomodulatory receptors, which in turn may help maintain an immature phenotype. MC-S and DM generated the liposomes. Data were analyzed using CBA software. 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